Research and development of therapeutic mAbs: An analysis based on pipeline projects

Geng, Xiaomei; Kong, Xiangjun; Hu, Hao; Chen, Jiayu; Yang, Feng‐Qing; Liang, Hongyu; Chen, Xin; Y, Hu

doi:10.1080/21645515.2015.1074362

Cited by 36 publications

(25 citation statements)

References 49 publications

(45 reference statements)

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“…Antibodies have evolved from being ancillary biochemical reagents in laboratory research to taking center stage as powerful drugs that are used in the clinic to treat cancer and immune-mediated disorders (1, 2). By the end of 2014, the list of 47 antibody therapeutics approved and marketed in the US and EU was growing at an average approval rate of 4 new products per year (3).…”

Section: Introductionmentioning

confidence: 99%

Fc-Mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models

et al. 2018

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A critical benchmark in the development of antibody-based therapeutics is demonstration of efficacy in preclinical mouse models of human disease, many of which rely on immunodeficient mice. However, relatively little is known about how the biology of various immunodeficient strains impacts the in vivo fate of these drugs. Here we used immunoPET radiotracers prepared from humanized, chimeric and murine monoclonal antibodies against four therapeutic oncologic targets to interrogate their biodistribution in four different strains of immunodeficient mice bearing lung, prostate, and ovarian cancer xenografts. The immunodeficiency status of the mouse host as well as both the biological origin and glycosylation of the antibody contributed significantly to the anomalous biodistribution of therapeutic monoclonal antibodies in an Fc receptor-dependent manner. These findings may have important implications for the preclinical evaluation of Fc-containing therapeutics and highlight a clear need for biodistribution studies in the early stages of antibody drug development.

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Section: Introductionmentioning

confidence: 99%

Fc-Mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models

et al. 2018

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“…The crystallizable or constant fragment (Fc) region of mAbs determines their effector function through the ability to bind Fc gamma receptors (FcγR) expressed on endogenous cells. 14…”

Section: S Truc Tur Al and Fun C Tional Fe Ature S Of Antibod Ie Smentioning

confidence: 99%

The pharmacology and therapeutic applications of monoclonal antibodies

Castelli

McGonigle

Hornby

2019

Pharmacology Res & Perspec

209

111

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Monoclonal antibodies (mAbs) have emerged as a major class of therapeutic agents on the market. To date, approximately 80 mAbs have been granted marketing approval. In 2018, 12 new mAbs were approved by the FDA, representing 20% of the total number of approved drugs. The majority of mAb therapeutics are for oncological and immunological/infectious diseases, but these are expanding into other disease areas. Over 100 monoclonal antibodies are in development, and their unique features ensure that these will remain a part of the therapeutic pipeline. Thus, the therapeutic value and the elucidation of their pharmacological properties supporting clinical development of these large molecules are unquestioned. However, their utilization as pharmacological tools in academic laboratories has lagged behind their small molecule counterparts. Early therapeutic mAbs targeted soluble cytokines, but now that mAbs also target membrane‐bound receptors and have increased circulating half‐life, their pharmacology is more complex. The principles of pharmacology have enabled the development of high affinity, potent and selective small molecule therapeutics with reduced off‐target effects and drug‐drug interactions. This review will discuss how the same basic principles can be applied to mAbs, with some important differences. Monoclonal antibodies have several benefits, such as fewer off‐target adverse effects, fewer drug‐drug interactions, higher specificity, and potentially increased efficacy through targeted therapy. Modifications to decrease the immunogenicity and increase the efficacy are described, with examples of optimizing their pharmacokinetic properties and enabling oral bioavailability. Increased awareness of these advances may help to increase their use in exploratory research and further understand and characterize their pharmacological properties.

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“…In most cases in vivo models can be limited in their ability to predict efficacy in humans, particularly due to differences in the pharmacokinetics of the molecules between humans and model animal species [110]. Geng et al reported that a large percentage of antibodies for anti-infective indications are ended in the early stage of discovery making them a high risk category in drug development [35]. Challenges in clinical efficacy and pharmacokinetics can be overcome by choosing appropriate format for the indication.…”

Section: Gram Positive Bacteria Targetsmentioning

confidence: 99%

Monoclonal Antibodies and Antibody Like Fragments Derived from Immunised Phage Display Libraries

Ubah¹,

Palliyil

2017

Recombinant Antibodies for Infectious Diseases

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Morbidity and mortality associated with infectious diseases are always on the rise, especially in poorer countries and in the aging population. The inevitable, but unpredictable emergence of new infectious diseases has become a global threat. HIV/AIDS, severe acute respiratory syndrome (SARS), and the more recent H1N1 influenza are only a few of the numerous examples of emerging infectious diseases in the modern era. However despite advances in diagnostics, therapeutics and vaccines, there is need for more specific, efficacious, cost-effective and less toxic treatment and preventive drugs. In this chapter, we discuss a powerful combinatorial technology in association with animal immunisation that is capable of generating biologic drugs with high affinity, efficacy and limited off-site toxicity, and diagnostic tools with great precision. Although time consuming, immunisation still remains the preferred route for the isolation of high-affinity antibodies and antibody-like fragments. Phage display is a molecular diversity technology that allows the presentation of large peptide and protein libraries on the surface of filamentous phage. The selection of binding fragments from phage display libraries has proven significant for routine isolation of invaluable peptides, antibodies, and antibody-like domains for diagnostic and therapeutic applications. Here we highlight the many benefits of combining immunisation with phage display in combating infectious diseases, and how our knowledge of antibody engineering has played a crucial role in fully exploiting these platforms in generating therapeutic and diagnostic biologics towards antigenic targets of infectious organisms.

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Research and development of therapeutic mAbs: An analysis based on pipeline projects

Cited by 36 publications

References 49 publications

Fc-Mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models

Fc-Mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models

The pharmacology and therapeutic applications of monoclonal antibodies

Monoclonal Antibodies and Antibody Like Fragments Derived from Immunised Phage Display Libraries

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